1. Haemoglobin synthesis (1)

University of Portsmouth - Introduction to Haemoglobin

Overview

  • Presenter: Gavin Knight

Learning Objectives

  • By the end of this session, you should be able to:

    • Describe the formation of the haemoglobin molecule.

    • Explain the basic structure of haemoglobin.

    • Recognize consequences of selected defects in haemoglobin synthesis.

    • Identify principal haemoglobin measurements included in the Full Blood Count (FBC).

Importance of Haemoglobin

  • Red blood cells (RBCs) are responsible for carrying oxygen (O2) from the lungs to tissues and carbon dioxide (CO2) back to the lungs.

  • Approximately 98% of the cytoplasmic protein in red blood cells is haemoglobin.

  • 65% of haemoglobin is synthesized prior to the extrusion of the nucleus.

  • Haemoglobin is classified as a metalloprotein, meaning it contains metal ions, crucial for its function.

  • Key haemoglobin measurements in FBC include:

    • Haemoglobin

    • Mean Cell Haemoglobin (MCH): normal range 27 – 32 pg.

    • Mean Cell Haemoglobin Concentration (MCHC): normal range 315 – 345 g/L.

Basic Structure of Haemoglobin

  1. Structure Type: Heterodimeric tetramer.

  2. Composition: Two alpha-like globin chains and two non-alpha globin chains.

  3. Haem Group: The iron-containing component essential for oxygen binding.

Haemoglobin Synthesis

  • The synthesis pathway of haemoglobin includes several key intermediates and enzymes:

    • Protoporphyrinogen IX → Protoporphyrin IX

    • Glycine + Succinyl CoA → forms d-aminolaevulinic acid.

    • Porphobilinogen

    • Hydroxymethylbilane

    • Uroporphyrinogen III

    • Coproporphyrinogen III

    • Ultimately producing Haem and Globin in the cytoplasm.

Porphyrias

  • Enzyme Deficiencies: Certain enzyme deficiencies lead to different types of porphyrias, including:

    • X-linked protoporphyria: Deficiency in ALA synthase.

    • Acute intermittent porphyria: ALA dehydratase deficiency leading to elevated Porphobilinogen (PBG).

    • Congenital erythropoietic porphyria: Resulting from Uroporphyrinogen III synthase issues.

    • Porphyria cutanea tarda: Linked to Uroporphyrinogen decarboxylase defects.

    • Hereditary coproporphyria: Due to Coproporphyrinogen oxidase deficiency.

    • Variegate porphyria: Relating to Protoporphyrinogen oxidase deficiencies.

    • Increased risk for skin and liver problems associated with these disorders.

Haem Structure

  • Haem is formed when iron is chelated into Protoporphyrin IX by ferrochelatase.

  • The iron at the center of the haem structure can exist in various oxidation states, affecting its function.

Summary

  • Synthesis Timing: Most haemoglobin is synthesized before the reticulocyte stage of maturation.

  • Structural Characteristics: Haemoglobin is identified as a heterodimeric tetramer, requiring alpha chains for its structure post-embryonic stage.

  • Synthesis Location: Occurs within the cytoplasm (ribosomes) and mitochondria, where iron is incorporated by ferrochelatase into haem subunits.